Hyperargininemia is considered to be the least common urea cycle disorder (UCD) encountered in clinical practice, with estimated incidence rates of 1 in 350,000-1,000,000 [1]. The pathogenesis stems from mutations in genes coding for the catalytic enzyme arginase that is necessary for the conversion of L-arginine to urea and ornithine [2] [3]. Hyperargininemia, like the majority of UCDs, is transferred through an autosomal recessive pattern of inheritance, but the clinical presentation differs from other UCDs in terms of the onset of symptoms and their severity [2] [4]. Namely, patients mainly start to develop first signs after infancy, in the period between ages 2 and 4, while severe hyperammonemia that is typical in other UCDs is often absent [2] [4]. Instead, a slowly progressive appearance of neurological manifestations is seen, starting with irritability, failure to thrive, feeding difficulties, and inability to reach appropriate developmental milestones [4] [5]. In the absence of proper therapy, more severe symptoms and signs are noted in a slowly progressive fashion - seizures (generalized tonic-clonic), progressive spastic diplegia, psychomotor and cognitive decline, as well as growth failure [1] [2] [4] [5]. In a subset of cases, episodes of vomiting and lethargy are observed [4]. Furthermore, liver diseases (cholestasis, liver failure, fibrosis, or even hepatocellular carcinoma) can be recognized in some cases of hyperargininemia [3] [6] [7].

• Pediatric Disease

  Aeglea is developing pegzilarginase, its lead investigational therapy, for the treatment of Arginase 1 Deficiency, which has received both rare pediatric disease and breakthrough therapy designation. [finance.yahoo.com]

• Failure to Thrive

  Failure to thrive and dysmorphic features were also seen. Conclusion: Hyperargininemia commonly manifests as regression, failure to thrive, spasticity, seizures with or without microcephaly. [go.gale.com]

  Main features include failure to thrive, signs of hyperammonemia (anorexia, irritability, tachypnea, lethargy, vomiting), and additional neurologic signs (progressive spastic quadriplegia, seizures, mental retardation, hyperactivity). [accessanesthesiology.mhmedical.com]

  Instead, a slowly progressive appearance of neurological manifestations is seen, starting with irritability, failure to thrive, feeding difficulties, and inability to reach appropriate developmental milestones. [symptoma.com]

  The onset of argininemia is typically insidious, with the symptoms – including spastic paraplegia, mental retardation, failure to thrive, and seizures – arising during childhood.[2–4] We describe the case of a Chinese patient with argininemia, who initially [journals.lww.com]

• Irritability

  This rapid increase in ammonia may lead to episodes of irritability, refusal to eat, and vomiting. In some affected individuals, signs and symptoms of argininemia may be less severe, and may not appear until later in life. [wikidoc.org]

  Main features include failure to thrive, signs of hyperammonemia (anorexia, irritability, tachypnea, lethargy, vomiting), and additional neurologic signs (progressive spastic quadriplegia, seizures, mental retardation, hyperactivity). [accessanesthesiology.mhmedical.com]

  Infants may be irritable, vomit and exhibit feeding problems. They may be less alert when given cow's milk. Some infants may refuse to eat. Argininemia will affect the central nervous system. [thinkgenetic.com]

  This rapid increase in ammonia may lead to episodes of irritability, refusal to eat, and vomiting. In some affected individuals, signs and symptoms of arginase deficiency may be less severe, and may not appear until later in life. [ghr.nlm.nih.gov]

• Hyperactivity

  The major symptoms of AD are all progressive and include psychomotor retardation, spastic tetraplegia where the lower limbs are more affected than the upper, hyperactivity, growth failure and seizures. [themedicalbiochemistrypage.org]

  Main features include failure to thrive, signs of hyperammonemia (anorexia, irritability, tachypnea, lethargy, vomiting), and additional neurologic signs (progressive spastic quadriplegia, seizures, mental retardation, hyperactivity). [accessanesthesiology.mhmedical.com]

  Hyperactivity. Behavior problems. Learning delays. Coma. Diagnosis: Genetic testing for argininemia is available. Genetic testing, also called DNA testing, looks for changes in the pair of genes that cause the condition. [medigoo.com]

  They include: Avoiding foods high in protein or a dislike of meat Loss of appetite Nausea or vomiting Behavior problems, including hyperactivity Mental problems (confusion, delusions, hallucinations, psychosis ) Diagnosis Most newborns in the U.S. are [webmd.com]

• Neurologic Manifestation

  We retrospectively evaluated the clinical onset, neurologic manifestations, progression of abnormalities, electroencephalographic abnormalities, and laboratory findings of 16 Brazilian patients with hyperargininemia. [pedneur.com]

  Instead, a slowly progressive appearance of neurological manifestations is seen, starting with irritability, failure to thrive, feeding difficulties, and inability to reach appropriate developmental milestones. [symptoma.com]

• Psychomotor Regression

  Symptoms are usually noticed in childhood: progressive spastic tetraplegia with predominant involvement of the lower limbs, seizures, ataxia, athetosis, psychomotor regression, hyperactivity, vomiting, hepatomegaly, and growth failure (1,2,5). [journals.lww.com]

• Cerebellar Sign

  H/o consanguinity in parents, H/O similar illness in family, if so their clinical features which included problems from birth, age at recognition of symptom, global delay, seizures, spasticity, extrapyramidal signs, cerebellar signs encephalopathy, skeletal [pediatricneurosciences.com]

Because of the rather rare occurrence of hyperargininemia in clinical practice, the diagnosis might be difficult to attain without adequate clinical suspicion. For this reason, a thorough clinical investigation comprised of a meticulously obtained patient history and a detailed physical examination is of critical importance. The course and progression of symptoms should be assessed with the parents, whereas signs of upper motor neuron damage (hyperreflexia, spasticity) are hallmarks of hyperargininemia on a neurological exam [4]. Furthermore, ataxia, toe walking, and cognitive impairment may be noted [4]. Magnetic resonance imaging (MRI) of the endocranium is a useful procedure in the evaluation of patients suffering from hyperargininemia, showing both cerebral and cerebellar atrophy. Microcephaly could be present in some cases. Electroencephalography (EEG) is also an important component of the diagnostic workup [4], but in order to confirm hyperargininemia, biochemical or genetic testing is necessary. The measured activity of arginase will reveal abnormally low values [4] [5].

• Neurophysiologic Abnormalities

  Laboratory findings, gait abnormalities, spastic paraparesis, and electroencephalographic and neurophysiological abnormalities remained quite stable over the follow-up. [ncbi.nlm.nih.gov]

  Results Laboratory findings, gait abnormalities, spastic paraparesis, and electroencephalographic and neurophysiological abnormalities remained quite stable over the follow-up. [moh-it.pure.elsevier.com]

1. Maramattom BV, Raja R, Balagopal A. Late onset arginase deficiency presenting with encephalopathy and midbrain hyperintensity. Ann Indian Acad Neurol. 2016;19(3):392-394.
2. Crombez EA, Cederbaum SD. Hyperargininemia due to liver arginase deficiency. Mol Genet Metab. 2005;84(3):243-251.
3. Schlune A, Vom Dahl S, Häussinger D, Ensenauer R, Mayatepek E. Hyperargininemia due to arginase I deficiency: the original patients and their natural history, and a review of the literature. Amino Acids. 2015;47(9):1751-1762.
4. Scaglia F, Lee B. Clinical, Biochemical, and Molecular Spectrum of Hyperargininemia Due to Arginase I Deficiency. Am J Med Genet C Semin Med Genet. 2006;0(2):113-120.
5. Hewson S, Clarke JT, Cederbaum S. Prenatal diagnosis for arginase deficiency: a case study. J Inherit Metab Dis. 2003;26:607–610.
6. Oldham MS, vanMeter JW, Shattuck KF, Cederbaum SD, Gropman AL. Diffusion Tensor Imaging in Arginase Deficiency Reveals Damage to Corticospinal Tracts. Pediatr Neurol. 2010;42(1):49-52.
7. Cederbaum SD, Yu H, Grody WW, Kern RM, Yoo P, Iyer RK. Arginases I and II: do their functions overlap? Mol Genet Metab. 2004;81(Suppl 1):S38–S44.